ch20 - Chemistry 140C Spring 2009 (K. Albizati) Chapter 20...

Chemistry 140C Spring 2009 (K. Albizati) 1 Chapter 20 – Carboxylic Acid Derivatives We have already seen a number of carboxylic acid derivatives and how to prepare them --- esters, anhydrides, acyl halides and amides. We have also seen that nucleophilic addition-elimination is a major reaction mode…. . ..…and that it can be acid- or base-catalyzed. The order of reactivity of the 4 major derivatives with a nucleophile like water (or just about any nucleophile) is quite clear: This is due to 2 reasons: -Leaving group ability -Resonance of the “L” group with the carbonyl Halides and carboxylates are the weakest bases and are therefore the best leaving groups under both acid and base-catalyzed conditions. Alkoxides and amine anions are fairly strong bases and are poor leaving groups and must be catalyzed by acids and bases with a lot of heat.

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Chemistry 140C Spring 2009 (K. Albizati) 2 Resonance with the L group with the carbonyl depends on the ability of the atom attached to the carbonyl to bear a positive charge. That is, electronegativity comes into play. The more of a resonance contribution the attached atom in L makes, the greater is the electron density at carbonyl carbon and the less reactive is the acyl group toward nucleophilic addition. Because positive charge character is distributed to L, this atoms’ ability to tolerate a positive charge determines how important this resonance is. In acyl halides, the atom is a very electronegative halogen and the resonance is not of great importance. In esters, the atom is oxygen, which is not as electronegative so resonance contribution is greater than for acyl halides. In anhydrides, the central oxygen can be delocalized into 2 carbonyls so there is less electron density at either carbonyl compared to an ester, thus making anhydrides more reactive than esters. In amides, the resonance contribution is substantial because nitrogen is the least electronegative atom of the group and can best take positive charge character. Hence, amides have a lot of electron density at the carbonyl carbon and are the least reactive of the carboxylic acid derivatives toward nucleophiles. This has enormous ramifications in biochemistry and molecular biology. Acidity of the α-hydrogens in Carboxylic Acid Derivatives Like aldehydes and ketones the hydrogens on the carbon attached to the carbonyl group have enhanced acidity due to resonance in the enolate anion: The relative acidities compared to a typical ketone like acetone are:

Chemistry 140C Spring 2009 (K. Albizati) 3 This has important ramifications to reactivity that we will see later in Chapter 23. Basicity of Carboxylic Acid Derivatives As you might expect, these functional groups are only weakly basic and it takes a strong acid to protonate them. Further, protonation takes place exclusively on the carbonyl oxygen due to resonance considerations: We will see this protonation phenomenon repeatedly in the rest of this chapter.

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